Urticaria is a common skin disorder involving mast cell activation and degranulation. Urticaria is classified according to its chronicity into acute and chronic forms. It may occur spontaneously or on exposure to a physical factor. In the latter case, the urticaria is classified as a physical urticaria. Physical urticaria may be induced by mechanical and applied pressure, exercise, or exposure to cold, heat, sun, water, or vibration. The pathologic basis of physicial urticarias in general remains unclear and a genetic basis for these disorders has not been elucidated. The purpose of this protocol is to investigate the mast cell dependent pathogenic mechanisms of physical urticaria, both to better understand how to manage urticarial inflammation and to explore the consequences of mast cell degranulation in human tissues. In these studies, adult and pediatric patients undergo standard challenge testing to verify their urticaria. Blood samples are obtained for the investigation of molecular and genetic pathways involved in the disease process. Following the clinical induction of urticarial manifestations, additional blood samples are collected to determine soluble mediators involved in pathogenesis. Photographic imaging studies are performed during challenge testing. Skin biopsies are obtained prior to and following challenge testing that are analyzed for biochemical and histological markers. Since the inception of the physical urticaria protocol in 2009, we have enrolled over 110 patients and 33 healthy subjects. All patients safely underwent challenge testing based on their history. Blood samples and skin biopsies have been collected and stored for biochemical, molecular and, when applicable, genetic analysis. Mast cell degranulation was verified by skin biopsy. The majority of the patients were challenge positive to either cold-induced, cholinergic, dermatographism, solar or vibratory urticaria. Recently, we characterized the mast cell dependent vascular response in skin following a cold stimulus in seven patients with cold-induced urticaria in comparison to control subjects. Laser-speckle contrast imaging, infrared and polarized-light colorimetry were used to simultaneously determine the temperature, blood flow and color patterns in patients at baseline after cold challenge and while treated with antihistamine. Evidence for mast cell degranulation was established by elevation of serum histamine levels and the localized release of tryptase in post-challenge urticarial biopsies. We found that the vascular response accompanying mast cell degranulation is rapid and extensive. At the tissue level, it is characterized by a uniform pattern of increased blood flow, thermal warming, vasodilation, and recruitment of collateral circulation. These vascular responses are modified by the administration of an antihistamine. We concluded that monitoring the vascular responses within tissues that are associated with mast cell degranulation provides additional insight into the evolution of the acute inflammatory response and offers a unique approach to assess the effectiveness of treatment intervention. In a prospective survey of subjects referred for physical urticaria challenge testing on this study, we have recently determined that more than one-third of the subjects were negative to the presumed physical stimulus reported by history to provoke urticaria. This finding highlights the value of objective testing in patients with a history of a physically induced urticaria in order to accurately assess disease status and therapy.